Solid pharmaceutical tablet

ABSTRACT

The invention relates to a solid pharmaceutical tablet for oral delivery, the tablet comprising calcium carbonate in an amount of more than 30% by weight of the tablet and organic water-insoluble components in an amount of more than 20% by weight of the tablet, wherein the tablet is designed to be masticated into a coherent residual containing the organic water-insoluble components, and wherein the tablet is adapted to release more than 80% of the calcium carbonate within 5 minutes of mastication.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/933,942, filed Mar. 23, 2018, and entitled A SOLID PHARMACEUTICALTABLET (Atty. Dkt. No. PATG60-34066), which is incorporated by referencein its entirety.

TECHNICAL FIELD

The invention relates to a solid pharmaceutical tablet for oral deliveryand a method of releasing an active pharmaceutical ingredient, such ascalcium carbonate, from a solid pharmaceutical tablet.

BACKGROUND

Tablets containing calcium carbonate are well-known. Such tablets aredesigned and used e.g. for gastrointestinal benefit. A challenge withsuch known tablets is that such tablets are typically most suitable forswallowing as such tablets include significant amounts of calciumcarbonate. These significant amounts of calcium carbonate would beexpected to lead to oral displeasure in terms of texture or mouthfeel ifthe tablets were to be administered as chewable tablets.

SUMMARY

The invention relates to a solid pharmaceutical tablet for oraldelivery, the tablet comprising calcium carbonate in an amount of morethan 30% by weight of the tablet and organic water-insoluble componentsin an amount of more than 20% by weight of the tablet, wherein thetablet is designed to be masticated into a coherent residual containingthe organic water-insoluble components, and wherein the tablet isadapted to release more than 80% of the calcium carbonate within 5minutes of mastication.

According to an embodiment of the invention, a solid pharmaceuticaltablet has been provided which enables an advantageous release ofcalcium carbonate into the oral cavity of a user. The release, obtainedthrough use of organic water insoluble components, which may bemasticated into a coherent residual containing the organicwater-insoluble components, is significant and the inventive tablet bothprovides a solution where a user may avoid swallowing the tablet whilestill obtaining a significant amount of calcium carbonate. At the sametime, it is also possible to obtain the desired release withoutinferring negative texture feeling by a user, which would usually beexpected when releasing such high amounts of calcium carbonate into themouth of a user by means of a chewable product.

Thus, the obtained texture is, un-expectedly, far from the chalkinessfeeling a user may have when chewing a tablet comprising large amountsof calcium carbonate or when introducing powdered calcium carbonate intothe oral cavity.

In other words, the inventive tablet is an attractive delivery vehiclefor calcium carbonate specifically targeting challenges with deliveryand release of calcium carbonate from a tablet.

The present inventive tablet may thus be regarded as a new deliveryvehicle for calcium carbonate, which is in particular advantageous whenusing calcium carbonate as an active pharmaceutical ingredient, i.e. aningredient intended for a specific pharmaceutical effect.

A further advantage, which may be obtained according to the provisionsof the invention, is a reduction of the risk of overdose. A usermasticating the inventive tablet may thus typically prolong masticationof the tablet due to the presence of the coherent residual, thereby atleast prolonging the time until a new tablet is applied. This is notunimportant, as sustained overdose of calcium carbonate over time canlead to hypercalcaemia. Symptoms of hypercalcaemia may include anorexia,thirst, nausea, vomiting, constipation, abdominal pain, muscle weakness,fatigue, mental disturbances, polydipsia, polyuria, bone pain,nephrocalcinosis, nephrolithiasis and in severe cases, cardiacarrhythmias. Extreme hypercalcaemia may result in coma and death.Persistently high calcium levels may lead to irreversible renal damageand soft tissue calcification.

The applied calcium carbonate may advantageously be a commerciallyavailable DC-grade (DC: Direct compressible) of calcium carbonate.

In an embodiment of the invention, the tablet comprises calciumcarbonate in an amount of 30 to 60% by weight of the tablet.

According to an advantageous embodiment the tablet may comprisesignificant amounts of calcium carbonate. The inventive tablet may thuscomprise calcium carbonate in an amount of 30 to 60% by weight of thetablet.

In an embodiment of the invention, the tablet comprises calciumcarbonate in an amount of 35 to 55% by weight of the tablet.

In an embodiment of the invention, the tablet comprises calciumcarbonate in an amount of 40 to 50% by weight of the tablet.

According to an advantageous embodiment the tablet may comprisesignificant amounts of calcium carbonate. The inventive tablet mayadvantageously comprise around 45% by weight of the tablet therebyfacilitating release of an effective amount of pharmaceutically activeingredient, i.e. the calcium carbonate, without either compromising theuser's ability or desire to invoke the release.

In an embodiment of the invention, the tablet is adapted to release morethan 85% of the calcium carbonate within 5 minutes of mastication of thetablet.

The tablet may thus be designed to release a significant amount of thecalcium carbonate, e.g. 85% of the carbonate contained within the tabletproduct within a very short time period. The fast though still delayedrelease may be regarded as a key for obtaining the desiredpharmaceutical effect, as an inferior textural sensation duringmastication would typically demotivate the user for continuedmastication and thereby reduce the desired pharmaceutical effect whichshould be obtained through released calcium carbonate.

The referred release of calcium carbonate may be determined in twodifferent ways within the scope of the invention, In Vivo relase or Invitro release.

In vivo release: 6 assessors were instructed to masticate each samplewith 60 chews per minute for a total mastication time of 3 to 10minutes.

The assessors were instructed not to eat or drink anything but water forthe last 30 minutes before the test. Prior to test start the assessorsrinsed their mouths with water.

For each sample tested, the assessors chewed a tablet for 3 minutes,another tablet for 5 minutes and yet another tablet for 10 minutes toproduce tablet residuals for each time point. This was repeated once toobtain replicates for each assessor at each time point in the test

In vitro release: The release of calcium carbonate in this example wasdetermined in vitro. The measurements were carried out according to theprocedure set forth in the Ph. Eur. 6th ed. 2.9.25, in a phosphatebuffer with pH=7.4, a mastication rate of 60 chew per minute, and withthe temperature of the medium set at 37° C. The mastication process wasinterrupted every minute to replace the phosphate buffer therebypreventing saturation of the buffer and simulating swallowing in the invivo mastication process.

For each sample one tablet was masticated at specified time intervals 3,5 and 10 minutes to produce tablet residuals for each time point. Thiswas repeated 6 times to obtain 6 replicates for each time point in thetest.

Calcium carbonate content of the residuals after mastication, in vitroor in vivo, can be determined by standard Atomic absorption spectroscopy(AAS). For analysis, a tablet residual was dissolved in a mixture ofhydrochloric acid (HCl) and toluene. Following proper dilution andfiltration, the acidic phase was passed through the AAS device analyzingfor Ca (at a wave length of 442.7 nm).

The release was then calculated by comparing the Ca content of theresidual after mastication with the Ca content of the non-masticatedtablet.

Alternatively, standard titration techniques may be used to determinethe calcium carbonate content before and after mastication.

In an embodiment of the invention, the tablet is adapted to release morethan 90% of the calcium carbonate within 5 minutes of mastication of thetablet.

In an embodiment of the invention, the tablet is adapted to release morethan 60% of the calcium carbonate within 3 minutes of mastication of thetablet.

In an embodiment of the invention, the tablet is composed of a pressedmixture of particles and/or granules.

According to an advantageous embodiment of the invention, the tablet maybe formed by a pressed mixture of particles and/or granules. This is inparticular relevant when the particles and granules are of a differentnature in terms of content and e.g. size, as these may both be pressedtogether for the purpose of forming a mechanically stable tablet andeven more importantly, be used as interacting exhibitors of calciumcarbonate.

A granule in the present context is understood as an agglomerate ofpowder/particles. A granule is thus a structure produced throughgranulation. This granulation process by itself is well-known within theart.

In an embodiment of the invention, the calcium carbonate and the organicwater-insoluble components are contained in different particles and/orgranules before tableting.

The above-mentioned effect of interacting exhibitors in relation tocalcium carbonate may be advantageously obtained when calcium carbonateof the tablet is contained in other particles that the particlescomprising the organic water-insoluble components. During mastication,such a configuration of an exhibiting tablet matrix may both invoke thatcalcium carbonate is immediately released but also that some of theimmediately released calcium carbonate is masticated mechanically intothe coherent residual and then later again at least partly released fromthe coherent residual.

In an embodiment of the invention, more than 80% of the calciumcarbonate is contained in particles and/or granules different from theparticles and/or granules comprising the organic water-insolublecomponents before tableting.

The calcium carbonate may thus be contained in different types ofparticles and/or granules, thereby obtaining a hybrid type of release,while still maintaining an overall very fast release and relativelycomplete release of calcium carbonate. A relatively complete release ofcalcium carbonate in the present context refers to that only a minorfraction of the originally contained calcium carbonate is stillcontained in the coherent residual at the given point of time afterinitiation of mastication.

In an embodiment of the invention, the tablet comprises organicwater-insoluble components in an amount of 20 to 50% by weight of thetablet.

The organic water-insoluble components may constitute a significantamount of the tablet, while still maintaining the desired fast releaseof calcium carbonate and while maintaining an attractive mouthfeel.

The invention furthermore relates to a solid pharmaceutical tablet fororal delivery, the tablet comprising an active pharmaceutical ingredientin an amount of more than 30% by weight of the tablet and organicwater-insoluble components in an amount of more than 20% by weight ofthe tablet, wherein the tablet is designed to be masticated into acoherent residual containing the organic water-insoluble components, andwherein the tablet is adapted to release more than 80% of the activepharmaceutical ingredient within 5 minutes of mastication.

According to an advantageous embodiment of the invention, the solidpharmaceutical tablet delivers an active pharmaceutical ingredient, suchas calcium carbonate. The active pharmaceutical ingredient may bereleased from the tablet with little or no oral displeasure and thepharmaceutical ingredient may therefore have a greater chance of successin terms of the intended result or treatment, simply due to the factthat a user of the tablet will be motivated for chewing the tablet. Thedesired pharmaceutical effect would of course be reduced if a user wouldtend to refrain from either using the tablet or refrain from masticatingthe tablet due to e.g. displeasure or bad taste.

In an embodiment of the invention, the active pharmaceutical ingredientis an ingredient that provides an oral and/or gastrointestinal benefit.

In an embodiment of the invention, the active pharmaceutical ingredientprovides an acid neutralizing action.

In an embodiment of the invention, the active pharmaceutical ingredientforms a complex with an auxiliary ingredient after oral administration.

Administration in the present context is understood as the process ofusing a drug in order to cause physiological changes, e.g. as prescribedby a doctor to treat or prevent a medical condition.

In an embodiment of the invention, the tablet comprises calciumcarbonate in an amount of more than 15% by weight of the tablet andorganic water-insoluble components in an amount of more than 25% byweight of the tablet, wherein the tablet is designed to be masticatedinto a coherent residual containing the organic water-insolublecomponents, and wherein the tablet is adapted to release more than 80%of the calcium carbonate within 5 minutes of mastication.

The invention furthermore relates to a method of releasing calciumcarbonate from a solid pharmaceutical tablet, the method comprising: a)providing a tablet comprising calcium carbonate in an amount of morethan 30% by weight of the tablet and organic water-insoluble componentsin an amount of more than 20% by weight of the tablet, b) masticatingthe tablet into a coherent residual containing the organicwater-insoluble components, c) generating fluid in the oral cavity, d)releasing more than 80% of the calcium carbonate to the fluid in theoral cavity within 5 minutes of mastication.

In an embodiment of the invention, the masticating of the tabletprovides a teeth cleaning benefit.

The tablet may thus provide a teeth-cleaning benefit from both thereleased calcium carbonate, but also due to the friction between theteeth and the coherent residual during mastication.

In an embodiment of the invention, the masticating the tablet does notprovide a chalkiness taste sensation.

The inventive tablet, which is an excellent oral exhibitor of calciumcarbonate, may advantageously be used as a “two-way” delivery system,which releases calcium carbonate from the tablet, and at the same timereleases calcium carbonate for incorporation into the coherent residualduring mastication, thereby providing a physical “release-buffer”, whichmay be regarded as a facilitator for the advantageous in-use texture ofthe product.

It was a surprise to the inventor of the present invention that it waspossible to obtain a release of calcium carbonate according to theinvention without providing a chalkiness taste sensation duringmastication. A relatively high release of calcium carbonate according tothe invention would be expected to result in a more pronouncedchalkiness sensation during mastication. This is highly surprising inview of conventional thinking. In fact, the high release of calciumcarbonate according to the invention is in itself highly surprisinggiven the content of organic water-insoluble components in theformulation according to the invention.

The pressing force applied during tableting of particles/granules into atablet may influence the chalkiness and the undesired chalkiness may bereduced when applying compression force or larger than 25 kN.

In an embodiment of the invention, less than 15% calcium carbonate ispresent in the coherent residual containing the organic water-insolublecomponents after 5 minutes of mastication.

In an embodiment of the invention, less than 15% calcium carbonate ismasticated into the coherent residual containing the organicwater-insoluble components after 5 minutes of mastication.

The inventive tablet, which is an excellent oral exhibitor of calciumcarbonate, may advantageously be used as a two-way delivery system,which both releases calcium carbonate from the tablet, and at the sametime releases calcium carbonate for incorporation into the coherentresidual during mastication, thereby providing a physical“release-buffer”, which may be regarded as a facilitator for theadvantageous in-use texture of the product.

In an embodiment of the invention, the release of calcium carbonateprovides an oral and/or gastrointestinal benefit.

DETAILED DESCRIPTION

In some embodiments of the invention, the tablet comprises calciumcarbonate and organic water-insoluble components. In some embodiments ofthe invention, the tablet comprises an active pharmaceutical ingredient,such as calcium carbonate, and organic water-insoluble components. Theorganic water-insoluble components according to various embodiments aredescribed in the following.

Water-insoluble components in the present context typically refer toelastomer, natural or synthetic resins or other water-insolublecomponents such as water-insoluble softener.

The term “organic” is used in its usual meaning within chemistry,particularly as the subject of compounds and matter within organicchemistry as opposed to inorganic chemistry.

As used herein, the phrase “tablet” refers to a tablet made bytabletting in a tabletting machine by pressing the tablet material toform the tablet. For example, the tablet material may be exposed to apunching means in a tableting machine, pressing e.g. granules and/orpowder to a gathered mass of pressed material.

The tabletting may be performed at a certain pressure, e.g. typicallydefined as compression force. Different types of tabletting machines areknown within the art, such as a rotary press device available by Fette.

As used herein, the phrase “granules” refers to entities made e.g. bygranulation, and may typically contain a plurality of particles adheredtogether.

By the phrase “texture” is meant a qualitative measure of thevisco-elastic properties of the tablet and of the overall mouth-feelexperienced by the user during the mastication process. Thus, the term“texture” encompasses measurable quantities such as hardness andelasticity as well as more subjective parameters related to thechew-feel experienced by a user.

“Calcium carbonate” in the present context primarily refers to directcompressible (DC) calcium carbonate although minor amounts of non-directcompressible (non-DC) calcium carbonate may be applied within the scopeof the invention.

Calcium carbonate may thus be applied as particles, but in the presentembodiments, calcium carbonate may typically be applied as a granulate.Calcium carbonate may thus typically be granulated with starch,maltodextrin, Poly Vinyl Pyrrolydone (PVP), gum Arabic/acacia or othersuitable binder in order to make the calcium carbonate directlycompressible.

The preferred calcium carbonate is thus DC grades, including e.g. CS90and CM90 from SPI Pharma. Other commercially available DC grades ofcalcium carbonate may be applied within the scope of the invention, suchas Scoralite LL250 DC 97PVP from Scora S.A.S or Calcium Carbonate DC 90Sfrom Lohmann.

In some embodiments of the present invention, the organicwater-insoluble components comprise, for example, elastomer in the rangeof 1-15% by weight of the tablet, natural and/or synthetic resin in therange of 5-35% by weight of the tablet, and further other organic waterinsoluble components in the range of 5-30% by weight of the tablet.

It is evident, that the overall total amount of these above organicwater-insoluble components must be mutually adjusted in order to fitrequirements with respect to tablet content of calcium carbonate,sweetener, flavor, etc.

In some embodiments of the present invention, the tablet comprisesnatural resins in an amount of 0.1 to 30%, such as 1 to 25%, such as 3to 25% or 5 to 25%, by weight of the tablet.

In some embodiments of the present invention, the tablet comprisesnatural resins in an amount of at least 10% by weight of the tablet.

In some embodiments of the present invention, the tablet is free ofnatural resins.

In embodiments of the present invention, the tablet comprises syntheticresins in an amount of 0.1 to 30%, such as 1 to 25%, such as 3 to 25% or5 to 25%, by weight of the tablet.

In embodiments of the present invention, the tablet comprises elastomerin an amount of at least 2% by weight of the tablet, such as at least 4%by weight of the tablet.

In embodiments of the present invention, the tablet comprises elastomerin an amount of less than 35% by weight of the tablet, such as less thanabout 25% by weight of the tablet, such as less than 20%, 15% or 10% byweight of the tablet.

In embodiments of the present invention, the tablet comprises one ormore flavoring agents, preferably in powdered form, selected from thegroup consisting of essential oils, essences, extracts, powders, acids,coconut, coffee, chocolate, vanilla, grape fruit, orange, lime, menthol,liquorice, caramel aroma, honey aroma, peanut, walnut, cashew, hazelnut,almonds, pineapple, strawberry, raspberry, apple, pear, peach, apricot,blackberry, cherry, pineapple, plum essence, clove oil, bay oil, anise,thyme, cedar leaf oil, nutmeg, cinnamon, peppermint, wintergreen,spearmint, eucalyptus, mint, or any combination thereof.

In embodiments of the present invention, the tablet comprises one ormore humectants, such as propylene glycol or glycerol.

In embodiments of the present invention, the tablet is provided with acoating.

In embodiments of the present invention, the tablet has a weight in therange of 0.1 to 10 grams, such as in the range of 0.5 to 4 grams or suchas in the range of 1.5 to 2.5 grams.

According to an embodiment of the invention, the tablet may comprisefiller. In embodiments of the present invention, the tablet comprises anadditional filler in an amount of 0.1 to 40% by weight of the tablet.

Elastomers provide the rubbery, cohesive nature to the tablet, whichvaries depending on this ingredient's chemical structure and how it maybe compounded with other ingredients. Elastomers suitable for use in thetablet of the present invention may include natural or synthetic types.

Elastomer plasticizers vary the firmness of the organic water-insolublecomponents. Their specificity on elastomer inter-molecular interaction(plasticizing) along with their varying softening points cause varyingdegrees of finished tablet firmness and compatibility with otheringredients. This may be important when one wants to provide moreelastomeric chain exposure to the alkane chains of the waxes. Theelastomer plasticizers may typically may resins, such as syntheticresins and/or natural resins.

The elastomers employed in the tablet may vary depending upon variousfactors such as the desired texture of the coherent residual (i.e. thetablet after mastication) and the other components used in theformulation to make the tablet. The elastomer may be any water-insolublepolymer known in the art. Illustrative examples of suitable polymers inthe tablet include both natural and synthetic elastomers. For example,those polymers which are suitable in the tablet include, withoutlimitation, natural substances (of vegetable origin) such as chicle gum,natural rubber, crown gum, nispero, rosidinha, jelutong, perillo, nigergutta, tunu, balata, guttapercha, lechi capsi, sorva, gutta kay, and thelike, and mixtures thereof. Examples of synthetic elastomers include,without limitation, styrene-butadiene copolymers (SBR), polyisobutylene,isobutylene-isoprene copolymers, polyethylene, and the like, andmixtures thereof.

Natural resins may be used according to the invention and may be naturalrosin esters, including as examples glycerol esters of partiallyhydrogenated rosins, glycerol esters of polymerized rosins, glycerolesters of partially dimerized rosins, glycerol esters of tally oilrosins, pentaerythritol esters of partially hydrogenated rosins, methylesters of rosins, partially hydrogenated methyl esters of rosins,pentaerythritol esters of rosins, synthetic resins such as terpeneresins derived from alpha-pinene, beta-pinene, and/or d-limonene, andnatural terpene resins.

In an embodiment of the invention, the resin comprises terpene resins,e.g. derived from alpha-pinene, beta-pinene, and/or d-limonene, naturalterpene resins, glycerol esters of gum rosins, tall oil rosins, woodrosins or other derivatives thereof such as glycerol esters of partiallyhydrogenated rosins, glycerol esters of polymerized rosins, glycerolesters of partially dimerised rosins, pentaerythritol esters ofpartially hydrogenated rosins, methyl esters of rosins, partiallyhydrogenated methyl esters of rosins or pentaerythritol esters of rosinsand combinations thereof.

In an embodiment of the invention a synthetic resin may includepolyvinyl acetate (PVAc) and/or vinyl acetate-vinyl laurate (VA-VL)copolymers

In an embodiment of the invention, the tablet may comprise one or morecomponents selected from the group consisting of bulk sweeteners,flavors, dry-binders, tabletting aids, anti-caking agents, emulsifiers,antioxidants, enhancers, absorption enhancers, high intensitysweeteners, softeners, colors, or any combination thereof.

In an embodiment of the invention, the tablet comprises sweeteners, suchas bulk sweeteners, sugar sweeteners, sugar substitute sweeteners,artificial sweeteners, high-intensity sweeteners, or any combinationthereof.

Suitable bulk sweeteners include both sugar and non-sugar sweeteningcomponents.

Bulk sweeteners typically constitute from about 5 to about 95% by weightof the tablet, more typically about 20 to about 80% by weight such as 30to 70% or 30 to 60% by weight of the tablet.

Useful sugar sweeteners are saccharide-containing components commonlyknown in the tablet art including, but not limited to, sucrose,dextrose, maltose, lactose, dextrins, trehalose, D-tagatose, driedinvert sugar, fructose, levulose, galactose, corn syrup solids, and thelike, alone or in combination.

As an example, sorbitol can be used as a non-sugar sweetener. Otheruseful non-sugar sweeteners include, but are not limited to, other sugaralcohols such as mannitol, xylitol, maltitol, isomalt, erythritol,lactitol and the like, alone or in combination.

High intensity artificial sweetening agents can also be used alone or incombination with the above sweeteners. For example, high intensitysweeteners include, but are not limited to sucralose, aspartame, saltsof acesulfame, alitame, saccharin and its salts, cyclamic acid and itssalts, glycyrrhizin, dihydrochalcones, thaumatin, monellin, stevioside(natural intensity sweetener) and the like, alone or in combination. Inorder to provide longer lasting sweetness and flavor perception, it maybe desirable to encapsulate or otherwise control the release of at leasta portion of the artificial sweeteners. Techniques such as wetgranulation, wax granulation, spray drying, spray chilling, fluid bedcoating, conservation, encapsulation in yeast cells and fiber extrusionmay be used to achieve desired release characteristics. Encapsulation ofsweetening agents can also be provided.

Usage level of the artificial sweetener will vary considerably and willdepend on factors such as potency of the sweetener, rate of release,desired sweetness of the product, level and type of flavor used and costconsiderations. Thus, the active level of artificial sweetener may varyfrom about 0.001 to about 8% by weight (such as from about 0.02 to about8% by weight). When carriers used for encapsulation are included, theusage level of the encapsulated sweetener will be proportionatelyhigher. Combinations of sugar and/or non-sugar sweeteners may be used inthe tablet formulation.

A tablet according to the invention may, if desired, include one or morefillers/texturisers including as examples, magnesium, sodium sulphate,ground limestone, silicate compounds such as magnesium and aluminumsilicate, kaolin and clay, aluminum oxide, silicium oxide, talc,titanium oxide, mono-, di- and tri-calcium phosphates, cellulosepolymers, such as wood or microcrystalline cellulose (MCC), andcombinations thereof.

A number of further tablet materials well known within the art may beapplied within the scope of the present invention. Such componentscomprise but are not limited to waxes, fats, softeners, fillers,flavors, anti-oxidants, emulsifiers, colouring agents, binding agentsand acidulants

The granules or some of the granules may for example consist or largelycomprise of organic water-insoluble components and such granules may bemanufactured by means of extrusion and under-water pelletizing.

The size of such granules of organic water-insoluble components mayaccording to the present invention be controlled by several factors suchas opening sizes, the tablet composition, tablet temperature andpressure drop, if a die plate is used in the extruder. Due to aninteraction between the pressurized tablet composition, temperature andfriction in the openings of the die device, the average diameter of theproduced granules are normally larger than the diameters of the openingsin the die device. The relation between the diameters of the openings inthe die device and the average diameters of granules produced from aspecific tablet composition may be determined by the skilled person onbasis of routine experiments.

According to the invention it is also possible to produce granules withdifferent average diameters by making granules with one diameter, andsubsequently mix the granules with different average diameters indesired proportions.

Although the openings of a die of an extruder device may havecross-sections of any desired shape, e.g. circular, oval, square etc.,it is in some embodiments preferred that the die device comprisesopenings with substantially circular cross-section and diameters in therange of 0.1 to 1.3 mm. A first set of openings can e.g. have a firstdiameter in the range of 0.07 to 0.7 mm, such as in the range of 0.15 to0.6 mm, and suitably in the range of 0.2 to 0.5 mm. A second set ofopenings can have a second diameter larger than said first diameter. Thesecond diameter is conveniently in the range of 0.4 to 1.3 mm, such asin the range of 0.7 to 1.2 mm.

In some embodiments the tablet granulating system further comprises adrying device. Powder sweetener or talk may be added to the granules ina final drying step. The drying device can be a conventional centrifugaldryer or another suitable dryer e.g. a fluid bed dryer. The dryingdevice can, for example, include a mixer. The powder sweetener may in anembodiment be sorbitol, which is mixed to the dried or partially driedgranules. Minor amounts of residual moisture on the surface of thegranules, e.g. 2% Wt. based on the total weight of the granules, maycontribute to the adherence of the sorbitol powder to the surface of thegranules. It is possible to use a conventional anti-agglomerating agentas e.g. talc, but sorbitol powder can function as an anti-agglomeratingagent, and at the same time serves as sweetener. Although sorbitol isfound to be most suitable, other bulk sweeteners based on polyols mayalso be suitable, e.g. mannitol, xylitol, hexa-resorcinol, maltitol,isomalt, erythriol, and lactitol.

In one embodiment the tablet granulating system according to theinvention further comprises one or more sieves adapted for removinggranules with an average diameter such as above 1.3 mm. The removal oflarger granules improves a subsequent tabletting process.

According to an embodiment of the invention at least the extruder and/orthe die device comprises means for controlling the temperature of thetablet composition. The means for controlling temperature can be coolingor heating devices, and may serve to facilitate the flow of tabletcomposition through the extruder and the die device. In an embodimentthe extruder comprises delivering means for delivering sweetener and/orflavour to the tablet composition in the extruder.

During extrusion of the tablet composition the differential pressurebetween the tablet composition in the extruder and the tabletcomposition in the liquid filled chamber, i.e. over the die device issuitably above 10 bar, such as above 18 bar, such as in the range of 25to 90 bar. The temperature of the tablet composition in the extruder mayfor example be in the range of 40 to 125° C., suitably in the range 50to 115° C. The temperature of the die device may for example be in therange of 60 to 250° C., suitably in the range 80 to 180° C. Thetemperature of the liquid in the liquid filled chamber is convenientlyin the range of 8 to 40° C. The optimum for the pressures andtemperatures in the method according to the invention may, however, maybe determined by the skilled person as a matter of routine. The optimumvalues for specific tablet compositions, varies of course, depending onthe composition.

The quick cooling in the air filled or water-filled chamber may act topreserve possible fragile ingredients in the tablet composition so thattheir qualities are better kept intact and conveyed into the granulesincluded in the final tablet product. This improved quality of thetablet composition in the granules improves the general composition ofthe tablet.

Granule fractions of different average weights may be produced with twodifferent setups, each producing a batch of granules of a particularaverage weight, followed by a blending of the fractions. It is alsopossible to design a die means with die openings of at least twodifferent sizes to simultaneously obtain granules with different averagediameter. Thus it is possible to obtain granules having differentweights. More than two different average weights may be obtained,depending on the design of the die means in use. It is for instancepossible to obtain granules with three, four or more different averageweights.

The granules may be cut in a very large liquid-filled chamber, in whichthe granules are also cooled. In some embodiments the cooling iscombined with transfer of the granules away from the chamber. This canbe done e.g. by cooling the cut granules in water during transfer fromthe liquid filled chamber to a de-watering device. The transfer timefrom cutting to de-watering can be less than 6 s. The advantage of thisis that water-soluble ingredients in the tablet composition are notunnecessarily washed out of the granules. Optionally, the total time ofcontact between granules and cooling water can be further limited toless than 4 s.

The inventive tablet may be formed by pressed particles and/granules.When these are tableted, bonds are established between the particles orgranules, thereby conferring a certain mechanical strength to thetablet. Of the particles/granules, the tablet comprises calciumcarbonate in an amount of more than 30% by weight of the tablet.

When pressure is applied to the particles/granules, the bulk volume isreduced and the amount of air is decreased. During this process energyis consumed. As the particles/granules come into closer proximity toeach other during the volume reduction process, bonds may be establishedbetween the particles or granules. The formation of bonds is associatedwith a reduction in the energy of the system as energy is released.

Volume reduction takes place by various mechanisms and different typesof bonds may be established between the particles or granules dependingon the pressure applied and the properties of the particles or granules.

Examples of organic water-insoluble components applicable for tablets ofthe present invention are described in the PCT/DK02/00461 andPCT/DK02/00462, hereby incorporated by reference.

The composition of organic water-insoluble components, which are admixedwith tablet ingredients as defined below, can vary substantiallydepending on the particular product to be prepared and on the desiredmasticatory and other sensory characteristics of the final product.However, typical ranges (weight %) of the above organic water-insolublecomponents are: elastomer in the range of 1-15% by weight of the tablet,natural and/or synthetic resin in the range of 5-35% by weight of thetablet, and further other organic water insoluble components in therange of 5-30% by weight of the tablet.

It is evident, that the overall total amount of these above organicwater-insoluble components must be mutually adjusted in order to fitrequirements with respect to tablet content of calcium carbonate,sweetener, flavor, etc.

Granulates of organic water-insoluble components may be manufacturedaccording to conventional methods or e.g. those described in thePCT/DK02/00461 and PCT/DK02/00462, hereby incorporated by reference.

The following non-limiting examples illustrate different variations ofthe present invention. The examples are meant for indicating theinventive concept; hence the mentioned examples should not be understoodas exhaustive for the present invention.

EXAMPLES Examples 1-7

Seven different samples, given samples numbers 101-107, of complexes ofwater insoluble organic compounds are provided in Examples 1-7. Thecompositions are given in table 1 and the samples were prepared by thefollowing process:

Elastomers and about ⅓ of the resin are mixed at 120° C. together withfiller in a pre-heated mixer having horizontally placed Z-shaped armsfor mixing. The fillers are talc or non-DC calcium carbonate. Themechanical action of the mixer causes shearing and grinding resulting insoftening of the elastomers.

When the elastomers are softened, more resin is slowly added to theelastomer, resin and filler until the mixture becomes homogeneous. Theremaining resin is then added to the mixer and mixed for 10-20 minutes.The softeners, i.e. emulsifier, wax and vegetable fat, are then addedand mixed for 20-40 minutes until the whole mixture becomes homogeneous.

After a total mixing time of about 45-60 minutes, the mixture issubjected to pelletizing in a standard under water pelletizing (UWP)unit resulting in coherent granules with an average diameter ofapproximately 1 mm.

The applied polyisobutylene may eg. be Oppanol B12, polyvinyl acetate(PVAc) may eg. be Vinnapas B 1.5 sp, VA-VL copolymers (vinylacetate—vinyl laurate copolymers) may eg. be Vinnapas B 500/20 VL,natural resin may eg. be Staybelite 5E or Piccolyte C85, softener mayeg. be hydrogenated vegetable fat such as hydrogenated sunflower oil,Bulk sweetener may eg. be sorbitol, flavor may eg. be menthol crystals.It is stressed that the specifically mentioned components are of coursea non-limiting disclosure intended to assist a skilled person inreproducing the present invention.

In case of Example 7 (sample no. 107), the homogeneous mixture is notsubjected to pelletizing but merely discharged into a pan and allowed tocool to room temperature.

Then the mixture is added to another mixer having horizontally placedZ-shaped arms for mixing operating at a temperature of about 40° C. Bulksweetener is added and mixed until a homogenous mass is obtained.

The mass is discharged and cooled by liquid nitrogen before beingintroduced to a milling device, in which the mass is milled to obtainparticulate material that is ready for tableting.

TABLE 1 Numbers are given in percent by weight of the tablet Raw Ex. Ex.Ex. Ex. Ex. Ex. Ex. material 1 2 3 4 5 6 7 Sample no. 101 102 103 104105 106 107 Organic Elastomers 18 21 21 10 10 5 16 water (butylinsoluble rubber and components polyisobutylene) Resins 38 44 44 50 5055 31 (polyvinyl acetate (PVAc), VA-VL copolymers and natural resins(ester gums and terpene resins) Softeners 23 21 21 22 23 20 19 (wax,fats, emulsifiers) Filler (talc) 18 11 17 20 14 Filler 12 15 (Calciumcarbonate) Bulk 20 sweetener Flavor 3 3 2 3 Total 100 100 100 100 100100 100

Example 8-14

Preparation of Tablets

Tablets, given sample numbers 1001-1007, using the compounds as providedin Examples 1-7, respectively, were prepared as follows:

The compounds of Examples 1-7 are present in the form ofparticles/granules.

The particulate compounds of Examples 1-7, further tablet compounds andthe DC-calcium carbonate are weighed into the proper amounts accordingto the exampled compositions of table 2.

The weighed amounts are then added to a Turbula mixer in a stainlesssteel container and blended at 50 rpm for 4 minutes and then addingmagnesium stearate and blending one additional minute.

The mixtures are then tableted by means of a Piccola RIVA DC-SC-041-2. AFette 3090i may also applied.

The resulting tablets according to Examples 8-14 are then obtained bytableting with a suitable pressure force at about 28-30 kN as maincompression force. The tablet weight is 1.8 g for all samples.

The applied bulk sweetener may e.g. be isomalt, high intensity sweetenermay eg. be sucralose, flavor may e.g. be spearmint in powder form. Alsohere, it is stressed that the specifically mentioned components are ofcourse a non-limiting disclosure intended to assist a skilled person inreproducing the present invention.

TABLE 2 Number are given in percent by weight of the tablet Raw materialEx. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 Ex. 13 Ex. 14 Sample no. 1001 1002 10031004 1005 1006 1007 Sample 101 30 15 (Ex. 1) Sample 102 33 18 (Ex. 2)Sample 104 40 (Ex. 4) Sample 105 45 (Ex. 5) Sample 106 33 (Ex. 6) Sample107 40 (Ex. 7) Calcium 35 45 45 45 45 30 16 carbonate DC Bulk 32 19 1919 12 27 36 sweetener High 0.5 0.5 0.5 0.5 0.5 0.5 0.5 intensitysweetener Flavor 2 2 2 2 2 2 2 Mg stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5Total 100 100 100 100 100 100 100

Example 15—In Vitro Release of Calcium Carbonate from Tablets

The release of calcium carbonate in this example was determined invitro. The measurements were carried out according to the procedure setforth in the Ph. Eur. 6th ed. 2.9.25, in a phosphate buffer with pH=7.4,a mastication rate of 60 chew per minute, and with the temperature ofthe medium set at 37° C. The mastication process was interrupted everyminute to replace the phosphate buffer thereby preventing saturation ofthe buffer and simulating swallowing in the in vivo mastication process.

For each sample one tablet was masticated at specified time intervals 3,5 and 10 minutes to produce tablet residuals for each time point. Thiswas repeated 6 times to obtain 6 replicates for each time point in thetest.

Calcium carbonate content of the residuals after mastication wasdetermined by standard Atomic absorption spectroscopy (AAS). Foranalysis, a tablet residual was dissolved in a mixture of hydrochloricacid (HCl) and toluene. Following proper dilution and filtration, theacidic phase was passed through the AAS device analyzing for Ca (at awave length of 442.7 nm).

The release was then calculated by comparing the Ca content of theresidual after mastication with the Ca content of the non-masticatedtablet.

Alternatively, standard titration techniques may be used to determinethe calcium carbonate content before and after mastication.

Results (averages of replicate results)

Release % 0 min 3 min 5 min 10 min 1001 (Ex. 8) 0 62 81 86 1002 (Ex. 9)0 70 91 95

Example 16—Assessment of Teeth Cleaning Capability of Samples 1001 (Ex.8) and 1002 (Ex. 9)

A test panel of 8 persons trained for sensory evaluation was used. Thetrained persons were instructed not to eat or drink anything but waterfor the last 30 minutes before the test. The test panel was instructedto masticate the samples at a rate of 60 chews per minute for a totalmastication time of 10 minutes.

Besides evaluation of standard sensory attributes such as softness andtaste intensity the trained persons were instructed to assess the teethcleaning capability of the samples by answering the question: “Is anytablet residue left in the teeth?” (yes/no) at distinct time pointsduring the mastication process.

The results of this assessment are provided in tables 3 and 4 below

TABLE 3 assessment of teeth cleaning capability 1001 (Ex. 8) 0 min ½ min1 min 2 min 3 min 5 min 10 min Assessor 1 N/A No No No No No No Assessor2 N/A No No No No No No Assessor 3 N/A No No No No No No Assessor 4 N/ANo No No No No No Assessor 5 N/A No No No No No No Assessor 6 N/A No NoNo No No No Assessor 7 N/A No No No No No No Assessor 8 N/A No No No NoNo No

TABLE 4 assessment of teeth cleaning capability 1002 (Ex. 9) 0 min ½ min1 min 2 min 3 min 5 min 10 min Assessor 1 N/A No No No No No No Assessor2 N/A No No No No No No Assessor 3 N/A No No No No No No Assessor 4 N/ANo No No No No No Assessor 5 N/A No No No No No No Assessor 6 N/A No NoNo No No No Assessor 7 N/A No No No No No No Assessor 8 N/A No No No NoNo No

Example 17—Assessment of Chalkiness, Ie. Calcium Carbonate Residue ofSamples 1001 (Ex. 8) and 1002 (Ex. 9)

A test panel of 8 persons trained for sensory evaluation was used. Thetrained persons were instructed not to eat or drink anything but waterfor the last 30 minutes before the test. The test panel was instructedto masticate the samples at a rate of 60 chews per minute for a totalmastication time of 5 minutes.

Besides evaluation of standard sensory attributes such as softness andtaste intensity the trained persons were in this test instructed toassess chalkiness, ie the feeling of calcium carbonate residue in theoral cavity, by answering the question: “Is any calcium carbonateresidue left in the mouth, ie is a chalkiness feeling present?” (yes/no)at distinct time points during the mastication process.

The results of this assessment are provided in tables 5 and 6 below

TABLE 5 assessment of chalkiness 1001 (Ex. 8) 0 min 1 min 2 min 3 min 5min Assessor 1 N/A No No No No Assessor 2 N/A No No No No Assessor 3 N/ANo No No No Assessor 4 N/A No No No No Assessor 5 N/A No No No NoAssessor 6 N/A No No No No Assessor 7 N/A No No No No Assessor 8 N/A NoNo No No

TABLE 6 assessment of chalkiness 1002 (Ex. 9) 0 min 1 min 2 min 3 min 5min Assessor 1 N/A No No No No Assessor 2 N/A No No No No Assessor 3 N/ANo No No No Assessor 4 N/A No No No No Assessor 5 N/A No No No NoAssessor 6 N/A No No No No Assessor 7 N/A No No No No Assessor 8 N/A NoNo No No

What is claimed is:
 1. A solid pharmaceutical tablet for oral delivery,the tablet comprising calcium carbonate and organic water-insolublecomponents in a calcium carbonate to organic water-insoluble componentsweight ratio of at least 0.6, wherein the tablet is designed to bemasticated into a coherent residual containing the organicwater-insoluble components, and wherein the tablet is adapted to releasemore than 80% of the calcium carbonate within 5 minutes of mastication,wherein the tablet comprises calcium carbonate in an amount of more than15% by weight of the tablet, wherein the tablet comprises bulk sweetenerin an amount of at least 5% by weight of the tablet, wherein the tabletis composed of a pressed mixture of particles and/or granules, andwherein more than 80% of the calcium carbonate is contained in particlesand/or granules different from the particles and/or granules comprisingthe organic water-insoluble components before tableting.
 2. The tabletaccording to claim 1, wherein the calcium carbonate to organicwater-insoluble components weight ratio is at least 0.9.
 3. The tabletaccording to claim 1, wherein the calcium carbonate to organicwater-insoluble components weight ratio is at least 1.3.
 4. The tabletaccording to claim 1, wherein the calcium carbonate to organicwater-insoluble components weight ratio is at least 1.4.
 5. The tabletaccording to claim 1, wherein the tablet comprises organicwater-insoluble components in an amount of more than 11% by weight ofthe tablet.
 6. The tablet according to claim 1, wherein the tabletcomprises organic water-insoluble components in an amount of 11 to 50%by weight of the tablet.
 7. The tablet according to claim 1, wherein thetablet comprises calcium carbonate in an amount of 15 to 60% by weightof the tablet.
 8. The tablet according to claim 1, wherein the organicwater-insoluble components comprise elastomer in a range of 1-15% byweight of the tablet.
 9. The tablet according to claim 1, wherein theorganic water-insoluble components comprise natural and/or syntheticresin in a range of 5-35% by weight of the tablet.
 10. The tabletaccording to claim 1, wherein the organic water-insoluble componentscomprise further other organic water insoluble components in a range of5-30% by weight of the tablet.
 11. The tablet according to claim 1,wherein the tablet comprises bulk sweetener in an amount of between 5 to70% by weight of the tablet.
 12. The tablet according to claim 1,wherein the tablet comprises bulk sweetener in an amount of between 20to 70% by weight of the tablet.
 13. The tablet according to claim 1,wherein bulk sweetener selected from sugar sweetener and sugar alcoholsweeteners.
 14. The tablet according to claim 1, wherein bulk sweetenercomprises at least one sugar alcohol sweetener selected from sorbitol,mannitol, xylitol, maltitol, isomalt, erythritol, and lactitol.
 15. Thetablet according to according to claim 13, wherein calcium carbonate andthe organic water-insoluble components are contained in differentparticles and/or granules before tableting.
 16. The tablet according toclaim 1, wherein the tablet comprises a further active pharmaceuticalingredient.
 17. The tablet according to claim 16, wherein the furtheractive pharmaceutical ingredient is an ingredient that provides agastrointestinal benefit.
 18. The tablet according to claim 16, whereinthe further active pharmaceutical ingredient comprises an antacid.
 19. Asolid pharmaceutical tablet for oral delivery, the tablet comprisingcalcium carbonate and organic water-insoluble components in a calciumcarbonate to organic water-insoluble components weight ratio of at least0.6, wherein the tablet is designed to be masticated into a coherentresidual containing the organic water-insoluble components, wherein thetablet is adapted to release more than 80% of the calcium carbonatewithin 5 minutes of mastication, and wherein the tablet comprises bulksweetener in an amount of at least 5% by weight of the tablet.
 20. Asolid pharmaceutical tablet for oral delivery, the tablet comprisingcalcium carbonate and organic water-insoluble components in a calciumcarbonate to organic water-insoluble components weight ratio of at least0.9, wherein the tablet is designed to be masticated into a coherentresidual containing the organic water-insoluble components, and whereinthe tablet comprises bulk sweetener in an amount of at least 5% byweight of the tablet, wherein the tablet is composed of a pressedmixture of particles and/or granules, and wherein more than 80% of thecalcium carbonate is contained in particles and/or granules differentfrom the particles and/or granules comprising the organicwater-insoluble components before tableting.